PROJECT SUMMARY/ABSTRACT Lupus is a chronic, often debilitating autoimmune disease that predominantly affects young women. Damage to the kidneys (lupus nephritis) is a serious and common complication of lupus, affecting approximately 50% of patients, and has been linked with poor patient prognosis and increased risk of premature death. Current treatments for lupus are based on suppressing the immune system and inflammation. Unfortunately, these treatments, which include corticosteroids, have serious side effects and in many patients do not adequately protect the kidneys, highlighting the need for new treatment approaches. Iron is an important component of the body, but when present in excess can cause damage to cells. Evidence suggests that iron metabolism may be abnormal in the kidneys of lupus patients, with a growing body of literature indicating that several iron metabolism proteins can serve as urinary biomarkers of lupus nephritis. Our published report demonstrates that iron accumulation is increased in the kidneys and that reducing body iron levels helps to protect the kidneys from developing injury in a mouse model of lupus nephritis. This proposal investigates the mechanisms by which iron promotes kidney injury in lupus, with our goal being to specifically block these damaging effects while maintaining normal iron homeostasis. Specifically, we propose that in lupus nephritis, enhanced filtration of iron sources, including transferrin, leads to glomerular and tubular injury including iron- induced cell death (ferroptosis), contributing to the progression of kidney injury in lupus nephritis. Ferroptosis is a recently described form of cell death and has never been studied or targeted in lupus. Our preliminary data show that one of the key mediators of ferroptosis, the enzyme acyl-CoA synthetase long chain family member 4 (ACSL4), is dramatically upregulated in glomeruli and renal tubules around the onset of albuminuria in mice with lupus, with further increases evident as injury progresses. We will conduct experiments in genetic and inducible mouse models of lupus nephritis to test the role of iron and ACSL4 in promoting both glomerular and tubular injury in lupus nephritis, and whether drugs targeting iron accumulation or players in the ferroptotic pathway can stop further progression of renal injury. Together, these experiments will provide important novel insights into the disease mechanisms underlying the progression of renal injury in lupus, and offer potential new therapeutic approaches to treating lupus nephritis.